Recently, researchers and clinicians have focused increased attention on a group of children with severe mood and behavioral dysregulation (SMD). These children are characterized by impairing symptoms that include abnormal baseline mood (i.e. irritability, anger, and/or sadness), hyperarousal (e.g. insomnia, agitation, distractibility), and increased reactivity to negative emotional stimuli. Because this syndrome shares many clinical features with bipolar disorder (BPD), there is considerable debate as to whether these children should be diagnosed with BPD. However, children with this syndrome lack the cardinal symptoms of BPD, and other DSM-IV diagnoses (ADHD, ODD, etc.) capture heterogeneous clinical populations that include many children who do not exhibit the symptoms noted above. Therefore, the goals of this project are 1) to identify reliably a group of children with severe mood and behavioral dysregulation in order to characterize them clinically and behaviorally and follow them longitudinally; 2) to conduct a double-blinded, placebo-controlled trial of lithium in this population; and 3) investigate whether lithium response, which has been associated with neurotrophic effects and with changes in phosphoinositide signaling in bipolar patients, has similar effects in this group of patients. Standardized interview modules and rating scales will be used to rate the clinical features of mood dysregulation. A double-blind, placebo-controlled trial of lithium will be conducted, and magnetic resonance spectroscopy (MRS) will be preformed before and after treatment. Approximately 15 patients have completed the treatment trial, and MRS scans have been obtained. In addition, data from standardized behavioral paradigms have been obtained on approximately 35 children with SMD in order to identify deficits in core psychological processes associated with the disorder. These data show that children with SMD have deficits in response flexibility and social information processing that are similar, but not identical to, those of children with BPD. Data also indicate that children with SMD differ from those with BPD in their psychophysiological and behavioral responses to frustration, although the affective responses of the two patient groups are similar. A post-hoc analysis of data from a longitudinal epidemiological study indicates that children with SMD are more likely than non-SMD children to meet criteria for ADHD and depression, but not BPD, in early adulthood. Finally, preliminary neuroimaging data indicate that children with BPD, but not those with severe mood dysregulation, have decreased amygdala volume compared to controls.